The tissue microenvironment plays a critical role in regulating inflammation. Extracellular matrix (ECM) breakdown products are not only a byproduct of inflammation but play an essential role in controlling the duration and intensity of the inflammation. As the ECM is degraded during inflammation, low molecular weight hyaluronan (LMW HA) fragments are generated that are normally cleared during the healing process. However, during continual inflammation there is ongoing tissue destruction and persistence of LMW HA fragments in the tissue microenvironment. In addition to LMW HA, adenosine is present in the tissue microenvironment following inflammation. Adenosine acts as a negative regulator of inflammation and tissue destruction specifically thorough adenosine A2a receptor (A2aR) engagement. We propose degraded hyaluronan, in the form of LMW HA fragments, plays an important role in modulating the magnitude and quality of an immune response by down-regulating the expression of the A2aR thereby preventing its anti-inflammatory effects. Thus, the outcome of inflammation is determined by the interplay between pro-inflammatory LMW HA and the anti-inflammatory A2a receptor. An understanding of the pathways underlying the ability of ECM to augment inflammation may lead to potential targets for pharmacologic intervention. We believe that our studies will identify a novel mechanism by which LMW HA down regulates the anti-inflammatory A2aR thus promoting inflammation leading to tissue fibrosis.